Thiolurethane quaternary ammonium salts and processes for preparing them



Patented June 16, 1953 PATENT ner-1 ca iTHIOLURETHANE QUA'IERNARY ,AMMO-:iNIUM' S LTS AND PROCESSESFOR PRE- PARING THEM [hr]. .Weijlard; and MaxTishler, Westfield, N. :J., assignors to Merck & 0.0., 511110.,'IRahway, :.N.,J.,

,a corporation of New Jersey iNo' Dr-awing".

1ApplicationjDecemberI3,1949, Serial No. 132,793

1 9,o,1aims. (ore- 0 45.5)

- "1 This invention is concerned generally with a new group ofantispasmodics relatedtoacholine. More particularly, .it relates vtoadimethyl-allgyl-B- (carbamylmercapto)ethylqammonium saltswherein;bo,th,of :thehydrogens ,attachedito the nitrogenqatomvof,thacarbamyl grogpingare recplacedby saturated hydrocarbon radicals; tothe g'processior preparing :these; novel quaternary ammonium salts :and,to thedntermediate products thus, obtained.

Compounds, analogous to the quaternary amomonium ,salts. herein.described but "wherein 50xygen Zis ,substitutedfior sulfur suchasrdibutoline -Slllfate 1( imetljiylethyl fiehydroxyethyl-ammoniv,um,sulfate :dibutylurethanel, .have previously been found to be effectiveantispasmodics. The lpresentlyflisclosed quaternary; Saltsare, ;however,greatlysuperior in antispasmodic effectiveness {to-said -oxygen;analogs, and areat the same time much less toxic. eMoreoiler these noyel:quaternary, salts :have been found-to be far superior to any. other;know is asmodics, -su. ,h.:;.as pa- ;paverine, Pavatrine gandSyntropan. Ifhese new salts haye -,also heengf und rtohavelzantitubercuwlar'activity.

'Iihes n ve qua ernar zdimcthylealky fi 4.(N,N disubsti.tutedearhamylmercaptwethyl anunonium salts may .be ,Chemically represented asfollows:

wherein R. is an alkylradicaLiRvand Rzare saturated. hydrocarbonradicalsand ii is -ananion.

. 1:2 "W e :have discovered that thesedimethyhalkylfi-(N,N=disubstituted.r-rcarbamylmercapto) ethyl.ammonium'salts, wherein the substituents attached to the nitrogen atomof theI-carbamyl grouping :are :saturated hydrocarbon radicals, can beprepared by reacting dimethyl-aminoethylthiol with an N,N-disubstitutedcarbamyl chloride of the formula:

-wherein "R1 and R2 are saturated hydrocarbon -radicals, forexample-adialkyl carbamylchloride such :as dibutyl carbamyl chloride,diamyl car- #bamyl chloride, and "the like, or a-dicycloalkylcarbamyl-chloride, such as dicyclohexyl carbamyl chloride, to produce athiolurethane of the formula:

-wherein-R1and R2 are saturated hydrocarbon radicals, and reacting saidthiolurethanewith an --alky1-ester *of an inorganic acid,;for example ana alk-yl iodide, such as ethyl -iodide, propy1 iodide,

-butyl iodide, amyl iodide, and the like, a dialkyl sulfate, ysuch asdiethyl sulfate, and the *like,

--to produce-a quaternary-salt of the formula:

wherein '?R 'is an alkyl radical, R1 and R2 vare -saturated 'lidrocarbon .radicals and X is an anion.

The 'dimethyl am'inoethylthiol starting material-can be prepared byreactingdimethylaminoethyl chloride ,andfiodium 'hydrosulfide asdescribed in Example '1 hereinbelow. ,"Ihe dialkyl -or dicycloalkyl'carbamyl chloride can be prepared-by reacting "the appropriatesecondary amine with "phosgene according to the procedure =set*;-forthin the illustrative examples and describedjin J. "Chem. fSoc. 'l94f7,3113. The jdimethyl aminoethylthiol and the dis ubstituted carbamylchloride can be preparedin purified form, if desired, by fractional'distillationflin vacuo. v The reaction between the dimethylaminoethylthiol and the,.calflfiiitfl yl chloride having twosaturatedhydrocarbon substituents attached to the nitrogen atom of the carbamylgrouping, for

example a-dialkyl-carbamyl"chloride such as dimove impurities.

about 3 hours.

butyl carbamyl chloride, diamyl carbamyl chloride, and the like, or adicycloalkyl carbamyl chloride such as dicyclohexyl carbamyl chloride,and the like, is ordinarily conducted in the presence of a hydrogenchloride acceptor. The hydrogen chloride acceptor is preferably anorganic base such as a compound containing a pyridine ring, such aspyridine, quinoline, picoline, and the like, and preferably an acceptorthat also acts as a solvent for the reactants. The reaction isconveniently carried out by heating wherein R1 and Riare saturatedhydrocarbon radicals. I

'This thiolurethane is then reacted with an 7 alkyl'ester of aninorganic acid as, for example a dialkyl sulfate, such as diethylsulfate, an alkyl iodide, such as ethyl iodide, n-propyl iodide, n-butyliodide, n-amyl iodide and the like, to

produce the corresponding quaternary ammonium salt of the formula:

wherein R, R1, R2 and X have the significance defined hereinabove. 1

The reaction between the-thiolurethane and l the dialkyl sulfate(preferably diethyl sulfate) is conveniently conducted by bringing thereactants together in diethyl ether solution at substantially roomtemperature. Under these conditions the reaction is ordinarilysubstantially complete in about 15 hours and the quaternarydimethylalkyl ,3 (N,N disubstituted -'-carbamyl-mercapto)ethyl ammoniumethyl sulfate which precipitates can be recovered by filtration.

When the thiolurethane. is'reacted withf an "alkyl iodide the reactionis ordinarily carried out by mixing the reactants in the absence of asolvent and agitating the resulting mixturelat a temperature of about25-30 C(foraperiod'of The mixture is ordinarily allowed to standovernight to insure completion of the reaction. The product, which isthe corresponding dimethyalkyl B (N,N disubstitutedcarbamylmercapto)ethyl-ammonium ence of ethanol. r V

Examples of these quaternary salts having the wherein R is an alkylradical R and. B12 Lar e iodide isthen converted to the correspondingsulfate by reaction with powdered silver sulfate in the pres- 4saturated hydrocarbon radicals and X is an anion, are the following:

(1) Dimethyl ethyl-QB (N,N dicyclohexylcarbamylmercapto) ethyl ammoniumethyl sulfate, also named dimethylethyl-B-thiob ethyl ammonium ethylsulfate dicyclohexylurethane;

Dimethyl n propyl {3 (N,N dicyclohexyl carbamylmercapto ethyl ammoniumsulfate, also named dimethyl-n-propyl-c-thiolethyl ammonium sulfatedicyclohexylurethane Dimethyl n butyl e 3 (N,N dicyclohexylcarbamylmercapto)ethyl ammonium sulfate, also named dimethyl-n-butyl-.fi-thiolethyl' ammonium sulfate dicyclohexylurethane;

(4) Dimethyl n amyl B (N,N dicyclohexyl carbamylmercapto) ethyl ammoniumsulfate, also named dimethyl-n-amyl- B-thiolethyl ammonium sulfatedicyclohexylurethane; r e Dimethyl ethyl B (N,N diamyl carbamylmercapto)ethyl ammonium sulfate, also named dimethylethyl-B-thidlethYl ammoniumsulfate diamylurethane; Dimethyl ethyl ,6 (N,N diamyl--carbamylmercapto) ethyl ammonium ethyl sulfate, also nameddimethylethyl-B-thiolethyl ammonium ethyl sulfatediamylurethane; 1Dimethyl ethyl [3 -;(N,N dicyclohexylcarbamylmercapto) ethyl ammoniumsulfate, also named dimethylthyl-B-thiolethyl ammonium sulfatedicyclohexylurethane; Dimethyl ethyl B (N,N dibutylcarbamylmercapto)ethyl ammonium iodide, also nameddimethylethyl-B-thiolethyl ammonium iodide dibutylurethane; Dimethyl{ethyl ,8 (N,N- dibutyl carbamylmercapto ethyl ammonium sulfate, alsonameddimethylethyl ,8 thiolethyl ammonium sulfate dibutylurethane.

Dimethyl ethyl B (N,N dicyclohexyl carbamylmercapto) ethyl a mm on i u miodide, also named dimethylethyl-fi-thiolethyl ammonium iodidedicyclohexylurethane; a Dimethyl n propyl B (N,N dicyclohexylcarbamylmercaptmethyl ammonium iodide, also nameddimethyl-n-propyl-fi-thiolethyl ammonium iodidedicycloxhexylurethane;-,ix 1' a Dimethyl 9 n butylq- 5 e (N,Ndicyclohexyl carbamylmercapto) ethyl ammo- I nium iodide, also named.pli'methyl-ln-butyl e-thiolethyl ammonium iodide dicyclohexylurethane;

Dimethyl namyl p (N,N- dicyc1ohexyl carbamylmercapto)ethyl ammoniumiodide, also nameddimethyl-n-amyl- V p-thiolethyl ammonium. idodidedicyclo hexylurethane; U Dimethyl ethyl (3 (N,N.- diamylcarbamylmercapto) ethyl ammonium iodide, also named dimethylethylp-thiol'ethy1 ammonium iodide diamylurethane.

Of particular interest are the first seven quaternary salts listed onthe precedingpa e which have been found to possessoutstandingantispasmodic activity.

These compounds were tested in comparison .with Dibutolinesulfate(dim'ethylethyl -.p.- hydroxyethyl ammonium sulfate dibutylurethanelecreate on isolated organs-for:ariiitspasmodic activity as .follows:rabbit intestine, ,iorn-inhibition of spon- .taneous. activity; guineapigluterus', .for inhibition :of spontaneousaacti vity; guinea-,pigizitestineyior 40- me./-kg.ifor f-Di'bu-tolina and stowed-marks.

inhibition -of ..contraction produced .by .spasmo- 15 injections of:compound? over a three-monthpegemc -.a-gents,..urecho1ine acetylcholine, .and in r'iod. -Eaoh injectionwas-2J5mgikg. twice-"daily someinstances .b arium; chloride. on' week days, with 2 single inj'ectionsof 5 mg s/ kg. .The results ,obtained rare summerized in .the -on'saturdaysand Sundays. A-rsimilar group -was following table giventhetsame dosa'ge ofiDibutoline, and-a third r r Inhibit-ionofContraetlons :Irihibitiontoi:Spontaneous; rot G. P. Intestine Tro-.Activity.of v duc'ed by Spasmogenic- -Agents LOOIHIJOHDG Q Urecl-1o1ineQ I R bbt V, BBIHJHI Int estine G P Uterus 'fiifig Chloride ++-l-+.+++++L +s+' -1+ .+=+H-.: -+s++ 7 .+.-l.-.++ 1 r +.:i.--:+ 7(DithiolmaSuliat 5- +.:r "'Dibutoline' Sulfate. I N

As evident from the: above table the novel qua- ;ternary salts describedin this application, and especially the dimethylallgyl fi-thiolethyl#ammo- "snium (ethyl) --sulf ate dicyclohexyleurethanes, .are :moreeffective antispasmodics than Dibutoline. :Of ,particular interest. isthe .quaternary salt, di- .methylethyl flathiolethyl-ammonium sulfate.dicyclohexyl urethane (compound "7) which .has beeniound tobe two-tothree-times as .potent as -Dibutoline in inhibitingatheaefiectofspasmogenic :agents on. isolatedguinea pig. intestine.

, .A large number of experiments. have "been perrformed on :isolatedvvuteri of 'aboth pregnant and -non .pregnant :guinea pigs.- Direct-eomparisons .have been ,made of the activity onthe isolated uter-usbetween compound 7, .Dibutoline, papav- ='erine,.Pavatrine,andssyntropan. In nearlyevery :test :compound 7 proved .to the :the mosteffective .of-:allof these agents, sometimes-being active .on

an organ which was relatively refractory to the:

other compounds. Moreover, compound 7 proved to be very effective inrelaxinguterine contractions stimulated (by urecholine, acetyl choline,histamine, pitocum, or'ergotamine tartrate. Compound 7 has beenadministered orally, 'subcutaneously, and intravenously to the dog withexteriorized intestinal loop. Good intestinal =antispasmodic effectshave been 'ob'serve'dafter administration by 'all "three :routes,ithough Jon --some;occasions oral administration. failed. {When-Pavatrine :was administered .orall yffor compari- ''son in twoexperiments, -it succeededfsonce iand failed;once. When Dibutolineiodide has been -administered orally in comparable .doses '(up totrials. In a'single experiment, :compound '7 (-2 -mg./kg..sucutaneouslyl, relaxed .the uterus of -anzintact anesthetized guineapig.

Compound 7 produces :mydriasis similar to .that dbserved with Dibutolinewhen applied topically itoathezcats eye, .in..5.% ;or .1-,% solution.vMydri- 'asis was :not produced; by administration of ;oral doses upto 2mg./kg. I

tithe acute toxicity :of compound 7 was tested umdiound 'to beapproximately;one =ha1f as. toxic aas .Dibutoline in mice treated withsingle doses "subcutaneously. Determination of .LDauw (the dosage .that":will kill Nonehalf of I the animals :treated). pf. the. atwoIzdr-ugssimultaneously on two grouprserved as luninjectedaoontrols. At the- .end-of three months, rtheigrowthratezof allrgroup was [identical and there.was...no evidence 10i toxicity. --Examination- .of ther-ats afteradministration;ior ,threemonths showed no divergence from normal inhemoglobin -red .cell count, .and wwhite cell count(total-anddifierential). .Nogross morphorlogicalchanges were.found-.atautopsy; except/for a'moderate degree vof local tissue:irritationzatrthe !site of injection (rats are particularly susceptibleto local irritation). .iNolocal irritation was observed indogs-receiving repeated injections.

.The antitubercular utility of the new :quaternary-saltsillustratedibyetheactivitiestobserved when compounds .-1 and .9 weretested .for in -vitr.o iactivityragainsta human .typezstrainofiMtuberculosis designated .aswI-IB'Z-RV. 'II-hesecompounds wereactiveat-lll micrograms ,peizmilliliter.

The following examples illustrate methods of carrying out thepresenttimrention but it is to be understood that these examples are:given for fpurposes or-illustration an'd not :of limitation.

xEmmv e chloride hydrocliloride wasdissolved sins-850ml. of-'watereand8-50 m l.-oi' aqueous sofdium' hy- 'drexi'de sdlution was a'dded. :Theresultingsolution was-extracted successively :with -1000;ml., 500-1111.,an'd aOO ml. :portions fof di'ethyl .eth'er'.

"The: extracts awere rcombine'cl and theu-ether iwas evaporated :under.ireduced .pressure toizproduce :approximatelyz'iOOagme. ofcrndesdimethylamin'o- :ethylchloride. 7 a

.2700 gm. (1-1.-2 :moies)1.oi sodium sulfide mono- -hydrate iw'asmeltedin a five-liter flask provided withialmeehanical stirrer,.reflux.condenser, ther- .mometecr .and gas inlet .tube. Hydrogen sulfide-wa-s,passed.into-.the molten mixture over aperio'd of 6 to 7..hoursduring which time the mixture stirred. rapidly and maintained at a''tem- Lperature' between "about '50 and The di-..methylacminoethylchloride (760 gms:) was-added dropwise 'to t'hereaction-mixture over --a period of approximately --2 hours during whichtime' the -'contents of the flask-were stirred rapidly maintained at-atempe'rature Lflf :5.0eB.0. C. .Llhe -resulting mixture was' then,heatedtou-QOx-lflfi 1 $0., th'eatediunder. reflux for;1;hour;andccooled. The

diffierentistrains ;oi'.;:mice :gavemfigure ein-about action m xt wextracted u e i elrwith -600 ml 300 ml., and 3001111. portions ofdiethyl ether, the extracts were combined and dried over anhydrouscalcium sulfate (Drierite) The ether was then evaporated from the dryether solution, and the-residual material was fractionally distilled.The fraction distilling at 120-140", C.

, (temperature in distilling flask 140-190 G.) was collected to produce199 gms. of crude dimethylaminoethylthiol (yield approximately ,30% oftheory).

85'0 gms. of crude dimethylaminoethylthiol (from several preparations)was distilled in vacuo using a 6-8 inch Vigreux column to produce 748gms. of substantially pure dimethylaminoethylthiol; B. P. 37-43 61/20mm.; recovery yield approximately 88%. Analysis. Calcd for C iI-IuNS: C,45.66; H, 10.54; N, 13.32.

Found: C, 45.44; H, 10.56; N, 13.06.

Example 2 1800 ml. of xylene were placed in a five-liter, three-neckedflask provided with a mechanical stirrer and thermometer. The xylenewascooled to 10 C. and 297 gms. (3 moles) of phosgene Was added. Asolution containing 516 gms. (4 moles) of n-dibutylamine dissolved in1030 ml. of xylene was added to the phosgene solution over a period ofapproximately 5 hours, said addition 1 being carried out while rapidlystirring the flask. contents and maintaining the reaction temperature atapproximately 5-10 C. .The reaction 'mixture was stirred at roomtemperature for an additional period of about 18 hours, the dibutylExample 3 I 35 gms. (0.33 mole) of pure dimethylah inoethylthiol (B. F.37-43" C./20 mm.) prepared as described in Example 1, was dissolved in250 ml.

of pyridine contained in a one-liter, three-necked flask equipped with amechanical stirrer and reflux condenser. 57.5 g. (0.30 mole) ofn-dibutylcarbamylchloride, prepared as described in Example 2, was addedto the flask contents. The resulting mixture was heated under reflux forapproximately 3 hours and was then evaporated to. dryness in vacuo. Theresidual material was dissolved in 200 ml. of water and the pH wasadjusted to 3 by adding 30 ml. of concentrated aqueous hydrochloric acidsolution. The resulting solution was extracted with four 100 ml.porti-ons of diethyl ether and the ether extracts were discarded. Theaqueous solution was made a1- kaline by adding thereto an'excess ofsodium carbonate, and the resulting solution was extracted with three100 ml. portions of chloroform. The chloroform extracts were combined,dried over anhydrous calcium sulfate (Drierite) and the chloroformevaporated. The residual material was heated at 100-110 C. at a pressureof 1 mm. to remove all traces of solvent thereby producing approximately'76 gms. of dimethylaminoethylthioldibutylurethane; yield approximately97%; of theory. 1

0 ethylammonium l pared as described in Example 4, was dissolved inEmmrlepel 75 gms.'(0;29 mole) of dimethylaminoethyl-'thioldibutylurethane, prepared as described in Example 3, was mixedwith 235 g.. (1.5 moles) of ethyl iodide. The mixture was stirred untilsolution was effiected and the resulting solution was ,M. P. 56 0.;yield approximately 96.6% of theory.

Example 5 116 gms. (0.278 mole) ofdimethylethyl-B-thiol iodidedibutylurethane, pre- 1100 ml. of 90% aqueous ethanol, and 60 gms.

dissolved in 2000 m1. of pyridine. was stirred andv heated under refluxat a tem- (0.19 mole) ofpowdered silver sulfate was added to thesolution.

The resulting mixture was stirred rapidly for 2 hours, the silver iodidewas removed by filtration and washed with three 50 ml. portions ofethanol. The combined filtrate and washings were evaporated in vacuo toa syrup. The syrup was dissolved in 4'00 n11. of water, the solution wasextracted with two 200 ml. portions of diethyl ether, and the extractswere discarded. The pH of the aqueous solution was adjusted to 6.7 bythe-addition of aqueous barium hydroxide solution, hydrogen sulfide waspassed into the solution to'precipitate residual silver, 5 gm. ofactivated charcoal was added, and the mixture was filtered. The filtratewas evaporated in vacuo to a syrup and .the residual material wassubjected to benzene distillation using three 150 ml. portions ofbenzene. The residual material was dried over sulfuric acid at apressure of 1 mm. to produce 83.8 gms. of dimethylethyl-p-thiolethylammonium sulfate dibutylurethane: yield approximately 89.3% of theory.Analysis.C'alcd for c', 51.99;.H, 9.39; N, 8.08. Found: 0, 51.78; H,

Example 6 Dicyclohexylamine was reacted with phosgene according to theprocedure described for reacting phosgene with n-dibutylamine in Example2. -After evaporation of the-xylene solvent, therehexylcarbamylchloride; M. P. -86" C.

781 gms.. (3.2 moles) of powdered dicyclohexylcarb-amylchloride wasadded to a solution containing 350 gms. (3.3 moles) ofdimethylaminoethylthiol (prepared as described in Example 1) The mixtureperature of -105 C. for a period of 3 hours,

and the mixture was then cooled to room temperature. The nearly-solidmass was dissolved in 1000 ml. of water and the aqueous solution "wasevaporated in vacuo at a temperature below '50 C.'until a mush resulted.This residual-material was treated in the manner described in Example 3to produce948 gms. of dimethylaminodescribed in Example- 4 161reactingdimethylethyltlfioldicyclohexylurethane; P.: 48.450?- 6.;

yield approximately 95% of theory. Example 7 948 gms. ofdimethyl'aminoethylthioldicyclohexylurethane; prepared as described inExample 6, .Was .reacted with. ethyl iodide, according. tothe proceduredescribed :in:-Examp le .4,,to produce-l465 gms.. of. dimethylethylrd-thiolethyl ammonium iodide dicyclohexylurethane; Pel90-19l9 C.;; yieldapproximately 98% of theory. Analysis. Calcd for O19Hs7O'N'2SL H2O; :.C,47.79; H, 8.02; N, 5.87. Found-:10; 4-790';HZ 7.78v';.N, 5.63.

7 Example 8 2715i ms. of?dimethylethyleg-thiolethylj an'1 monium iodidedicyclohexylurethane,.preparedlas described in Example 7, wasreacted'with silver sulfate according. to the procedure described inExample 5 to produced-188 gms. of-dimethylethyl- 2U B-thiolethylammonium sulfate dicyclohexylurethane; M. P. 1'43'-144 C.; yieldapproximately 97% "of'theory. AnalysisP-Calcd'for.

31 gms. of dimethyl'aminoethylthioldicyclo hex-ylureth'a-ne prepared asdescribedii'n': Example 6, was reacted with- '85 -gm's5- ofn=propyliodide',*. utilizingsubstantially-the same procedure 1 as thatamino'ethylthioldibutylurethanewith ethyl iodide, to produce gmsz ofdimethyl -n-rpropyl-p thiolethyl ammonium iodide dicyclohexy-lurethane;M. P. 149-151 CI; yieldapproximately 41.7% of theory. Analysis.Calcd forC, 49.78; H, 8.15; N, 5.80. Found: C, 49.63; H, 7.99% N", 5.82} 1 20gms; of dimethyl-n-propy-ll-B-thiolethyl.am monium: iodide.dicyclohexylurethane was .ireacted with silver. su1fate,.accordingtoytheprocedure describedr in Example. 5,.to. produce 16.41 gms.-ofdimethyl-n-propy1=prthiolethyl ammonium sulfate dicyclohexylurethane;137-139 C.; yield ap proximately 85% of theory. Analysis.'-Calc"d forGwI-IvaOtNtSa-fififi (33521482 11; 9.91 N,- 6512 H2O, 11.80. Eound.-:'5?r.61 H; 9. 0; N, 6.37; H2,O.,,11 .44.,

Example 1 2 28.5 gms. of dimethyl-n-butyl-p-thiolethyl ammonium iodidedicyclohexylurethane was reacted with silver sulfate, according to theprocedure described in Example 5, to produce 23.7 gms. ofdimethyl-n-butyl-fl-thiolethyl ammonium sulfate dicyclohexylurethane; M.P. 99-99.5 C.; yield approximately 87% of theory. Analysis.-Calcd forC42Ha2OsN4Sa.6H2O; 'C, 53.47; H, 10.04; N,

Emdmple'id 31- gms.: ofdimethylamino'ethylthioldicycloe hexylurethane;prepared asrdescribed in: Example:

6;=w.as reacted with: neamyl'iodide; utilizing'thesubstantially.sameeprocedure as thatdesc'ribed in Example 4;. to. produce? 36' gms;of; dimethyli-neamyl-fi-thiolethyl ammonium." iodide?dicyclohexylurethane; M.-P. 179-18050; yield approximately 71% oftheory: Analysis.-Calcd for Cal-1439172315; C,- 51:75:1Hy8z49; 5248.Found: C,file-96;.151;..82331N 6.4 i

" EwdmpleMV mcnium iodide; dicyclohexylurethane, prepared I Eem 'li i"31 gms.. (0.1:mole) of dimethylam-inoethylthiol dicyclohexylurethane,preparedias described in? Example 6,..Was? dissolved in: 200. mlz; ofd-iethyl: I ether,. 31-. gms. 0.2 i mole) O'fe dicthy1 sulfate. was

added;. and. ther-mix-turerwasmllowedate standlat room'temperaturevoyernight; -The; crystalsi thatf formed.- were-recoyeredbyrfiltrationy.washedawithi Q n-Diamylamine was reacted with phosgenednrthe. presence. ofxylene,. utilizing. substantially the; same proceduredescribed-for reacting; n.-di-:-

butylamine with.phos ei e 'inrExample 2;;and;;the-

residual. material 01012911116617. after evaporation .of. the. xylene.was fractienally; dis'tilledr in:v vacud using a Vigreux columntovproducer diamyl.--- carbamylchloride; B. P. 112-114 C./1:mmi

' 62.6 .gmsof .diamylcarbamylchloride; preparedasdescribed.on--:theapreeedingg page; was. reacted with.v 33;. gms., of:.dimethyla-minoethylthiol;, prepared. as :describedvimExample r1, and 1the; react-- tion product was treated in substantially the same manneras described in Example 6, to pro-v duce 75.6 gms. ofdimethylaminoethylthioldiamylurethane, which was obtained as a liquid;

yield approximately 94% of theory.

Example 17 60.6 gms. of dimethylaminoethylthioldiamylurethane, preparedas described in Example 16, was reacted with ethyl iodide, utilizingsubstantially the same procedur as that described in Example 4, toproduce gms. of dimethylethylc-thiolethyl ammonium iodide diamylurethanewhich was obtained as an amorphous mass; yield approximately 97% oftheory. Analysis.-Calcd for C17H3'1ON2SI2 C, 45.94; H, 9.39; N, 6.30.Found: C, 45.89; H, 8.02; N, 638.

Example 18 90 gms. of dimethylethyl-p-thiolethyl ammonium iodidediamylurethane, prepared as describedovernight.

in Example 17, was reacted with silver sulfate,

utilizing substantially the same procedure as that described in Example5, toproduce 69 gms. of dimethylethyl-;8 thiolethyl ammonium sulfatediamylurethane; M. P. 124125 0.; yield approximately 91% of theory.Analysis.-'Ca1cd for C34H7406N4S3.1.5H20'2 H20, 3.56. Found: H20, 3.85.Sample dried to constant weight at 80 C./1 mm. AnaL-Calcd forC34H74O6N'4S32 N, 7.67. Found: N, 8.18.

' Example 19 15 gms. of dimethylaminoethylthioldiamylurethane, preparedas described in Example 16, was dissolved in 100 ml. of diethyl ether,15.4 gms. of diethyl sulfate was added to the solution and the resultingmixture was allowed to stand No crystallization took place. The mixturewas then heatedunder reflux for an additional 24 hours, without anyformation of crystals.

The ethereal mixture was extracted with two 25 ml. portions of water,the combined aqueous extracts were washed with ether and the etherlayers were-discarded. The pH of the aqueous" solution was adjusted to6.4 by the addition of 10% aqueous barium hydroxide solution, a smallamount of activated charcoal was added, and the mixture was filtered.The traces of barium ion were removed'from the filtrate by adding aminute amount of ammonium sulfate and a slight turbidity was removed byadding activated charcoal and filtering. The solution was evaporatedinvacuo to a syrup and the syrup was air-dried toconstant weight. Duringthe drying period, the syrup crystallized slowly, and the crystallinemasses were broken up during the drying pe-' riod. There was thusobtained 12 gms. of dimethyl-fi-thiolethyl ammonium ethyl sulfatediamylurethane; M. P. 55-56 C.; yield approximately 55% of theory.Analysis.'Calcd for C19H42O5N2Sa /gI-I2O: C, 50.51; H, 9.59; N, 6.19;E20, 1.99. Found: C, 50.20; H, 9.08; E20, 1.85.

' Modifications may be made in carrying out the present inventionwithout departing from the spirit and scope thereof. Insofar as thesechanges and modifications are within the purview of the annexed claimsthey are to be considered part of our invention. I

We claim: I 7

lqThe process which comprises reacting dimethylaminoethyl thiol with-acarbamyl chloride having two saturated hydrocarbon substituents attachedto the nitrogen atom of thecarbamyl- 5 12 grouping to produce athiolurethane er: the for-=- mula:

R1\ (I? I CH3 N-CSOH2CH:N'

R, CH3 V wherein R1 and R are saturated hydrocarbon radicals, andreactingsaid thiolurethane with an alkylester of an inorganic acid toproduce a quawherein R1 and R2 have the significance abovedefined, R isan alkyl radical, and X is an anion.

2. Quaternary salts having'the formula: T

N OS-CHaCHaNOHz QR, f V x @H. Y wherein R1 and R2 are saturatedhydrocarbon radicals, R is an alkyl radical, and X is an anion.

3. Dimethylalkyl-fi-thiolethyl' ammonium sulfate dialkylurethanes. 4.Dimethylalkyl-fi thiolethyl ammonium sulfate dicycloalkylurethanes.

5. Dimethylethyl-fi-thiolethyl ammonium sul, fate dicyclohexylurethane.

6. Dimethylethyl-p-thiolethyl ammonium eth-I yl sulfatedicyclohexylurethane.

7. Dimethyl-n-propyl- 8-th.iolethyl ammonium sulfatedicyclohexylurethane.

8. Dimethyl-n-butyl- 8-thio1ethy1 ammonium sulfate dicyclohexylurethane.

9. Dimethyl n amyl-fl-thiolethyl ammonium sulfate dicyclohexylurethane.7

Q JOHN WEI JLARD.

' f OTHER REFERENCES" Soc. Chem. Ind. (Br.). 537,105, April 14,1947.

1. THE PROCESS WHICH COMPRISES REACTING DIMETHLAMINOETHYL THIOL WITH A CARBAMYL CHLORIDE HAVING TWO SATURATED HYDROCARBON SUBSTITUENTS ATTACHED TO THE NITROGEN ATOM OF THE CARBAMYL GROUPING TO PRODUCE A THIOLURETHANE OF THE FORMULA: 